The kindey is the major organ responsible for the removal of fluoride from the body. As such, the extent of tubular reabsorption of fluoride filtered at the glomerulus can influence total body fluoride metabolism and toxicity by regulating fluoride concentrations in soft and hard tissues. Recent experiments by the author have led to the hypothesis that urinary pH is the key variable in determining the renal reabsorption of fluoride. Preliminary work has shown that the fraction of filtered fluoride that is reabsorbed can be controlled between 30% and 95% (excretion 5% and 70%) by manipulating urinary pH. Studies are proposed to test the hypothesis and to determine the influence of variations in acid-base status on: 1) the mechanism of renal fluoride reabsorption; 2) localization of the nephron site for fluoride reabsorption; 3) fluoride balance; 4) body fluid concentrations of fluoride; 5) fluoride uptake by bone and teeth; and 6) dental fluorosis. These studies will use rats and dogs. Alterations in acid-base status will be induced by acute and chronic administration of NH4Cl and NaHCO3, by manipulating respiration, and by giving acetazolamide. Several experimental approaches will be used, including constant infusion renal clearance methods, stop-flow techniques, and long-term balance studies. The proposed research can: 1) identify the major determinants and sites for the renal reabsorption of fluoride; 2) identify acid-base status as a major variable to be controlled by future investigators; 3) suggest a more rational treatment for excessive exposure to fluoride; and perhaps, 4) account for the variation between individuals, and studies, in caries reduction and in the incidence of dental fluorosis.